Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials.

Concerns about growth retardation and unknown effects on long-term brain development with stimulants have prompted interest in polyunsaturated fatty acid supplementation (PUFA) as an alternative treatment. However, randomized controlled trials (RCTs) and meta-analyses of PUFA supplementation in ADHD have shown marginal benefit, and uncertainty exists as to which, if any, PUFA might be effective in alleviating symptoms of ADHD. We conducted an updated meta-analysis of RCTs in ADHD together with multivariable meta-regression analyses using data on PUFA content obtained from independent fatty acid methyl ester analyses of each study PUFA regimen. The PubMed, Embase and PsycINFO databases were searched with no start date and up to 28th July 2013. Study inclusion criteria were: randomized design, placebo controlled, PUFA preparation as active intervention, reporting change scores on ADHD rating-scale measures. Rating-scale measures of inattention and hyperactive-impulsive symptoms were extracted, study authors were contacted to obtain missing data, studies not reporting negative findings had these data imputed, and study quality was assessed using the Jadad system plus other indicators. Random-effects models were used for pooled effects and for meta-regression analyses. Standardized mean differences (SMD) in inattention, hyperactive-impulsive and combined symptoms were assessed as rated by parents, teachers or all raters. The influence of study characteristics and PUFA regimen content was explored in multivariable meta-regression analyses. The overall pooled estimate from 18 studies showed that combined ADHD symptoms rated by all raters decreased with PUFA supplementation; SMD -0.192 (95% CI: -0.297, -0.086; P<0.001). However, when analyzed by rater, only parent-rated symptoms decreased significantly. Multivariable meta-regression showed that longer study duration, γ-linolenic acid (GLA), and the interaction between GLA and eicosapentaenoic acid (EPA) were associated with significant decreases in inattention; however, PUFA regimen content was unrelated to changes in hyperactive-impulsive symptoms. Certain fatty acids present in placebo preparations may potentially have been psychoactive. This meta-analysis provides modest evidence of PUFA effectiveness in ADHD, especially GLA and EPA for inattention symptoms; however, evidence of reporting bias, publication bias, variable methodological quality, and use of potentially psychoactive placebos limit the generalizability of these findings.